efficacy, safety and tolerability of azd9977 and dapagliflozin in participants with heart failure and chronic kidney disease

Conditions: Heart Failure; Chronic Kidney Disease

Summary: the purpose of the study is to evaluate the efficacy and safety of azd9977 in combination with dapagliflozin compared with dapagliflozin alone and to assess the dose-response relationship, dapagliflozin alone and 3 doses of azd9977 combined with dapagliflozin on urinary albumin to creatinine ratio (uacr). the study will be conducted in participants with heart failure (hf) with left ventricular ejection fraction (lvef \[below 60%\]) and chronic kidney disease (ckd) with estimated glomerular filtration rate (egfr \[between ≥ 20 and ≤ 60 ml/min/1.73 m\^2, with at least 20% of participants with egfr ≥ 20 to \<30 ml/min/1.73\^2 and a maximum of 35% of participants with egfr ≥ 45 ml/min/1.73 m\^2\]).

after screening, eligible participants will undergo a run-in period where all participants receive dapagliflozin for up to 7 weeks depending on pre-study use of sglt2i or not. at the end of the run-in period, eligible participants will be randomly assigned with a 1:1:1:1 ratio to receive once daily administration of one of the following 4 study treatments group for 12 weeks. to ensure blinding, the study treatment will be administered in the form of 3 oral capsules of azd9977 or placebo and 1 oral tablet or dapagliflozin. 1. azd9977 dose a + dapagliflozin 10 mg 2. azd9977 dose b + dapagliflozin 10 mg 3. azd9977 dose c + dapagliflozin 10 mg 4. dapagliflozin 10 mg participants will be randomized to one of the above treatment group, according to type 2 diabetes mellitus \[t2dm (yes/no)\] and egfr (≥ 20 to \<30 ml/min/1.73\^2; or ≥ 30 to \< 45 ml/min/1.73\^2; or ≥45 ml/min/1.73\^2). the total duration of participation will be approximately 22 to 24weeks.

Eligibility criteria:
inclusion criteria: participants are included in the study if any of the following criteria apply: * documented diagnosis of stable symptomatic hf (new york heart association class ii-iii) at screening, and a medical history of typical symptoms and signs of hf in those who are currently receiving loop diuretic treatment * left ventricular ejection fraction \<60% documented by the most recent echocardiogram or cardiac magnetic resonance imaging within the last 12 months prior to screening * stable background treatment for hf, hypertension, diabetes mellitus or renal disease according to guidelines * n-terminal-pro-brain natriuretic peptide (nt probnp) ≥300 pg/ml for participants with sinus rhythm at screening; and nt probnp ≥600 pg/ml for participants with atrial fibrillation/flutter at screening * the egfr ≥30 and ≤60 ml/min/1.73\^2 (by ckd- epi formula) and uacr ≥30 mg/g (3 mg/mmol) and \<3000 mg/g (300 mg/mmol) * body mass index less than 40 kg/m\^2 * serum/plasma k+ level ≥ 3.5 and \< 5.0 mmol/l within 10 days prior to randomization * serum/ plasma na+ level within normal reference values within 10 days prior to randomization * systolic blood pressure should be at protocol defined range at randomization (visit 3), with no change to antihypertensive treatments in previous 3 weeks * male or female of non-childbearing potential * all participants must follow protocol defined contraceptives procedures exclusion criteria: participants are excluded from the study if any of the following criteria apply: * primary glomerulopathy, vasculitic renal disease, prior dialysis or unstable rapidly progressing renal disease, autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasm antibody-associated vasculitis * participants with currently decompensated hf requiring hospitalization for optimization of hf treatment and are not on stable hf therapy at the time of enrollment * hf due to cardiomyopathies * high output hf (e.g., due to hyperthyroidism or paget's disease) * hf due to pericardial disease, congenital heart disease or clinically significant uncorrected primary cardiac valvular disease or planned cardiac valve repair/replacement * participants with uncontrolled diabetes mellitus (glycated hemoglobin \>10%) * participants with type 1 diabetes mellitus * intermittent or persistent 2nd or 3rd degree atrioventricular block, sinus node dysfunction with clinically significant bradycardia or sinus pauses, not treated with a pacemaker * history of any life-threatening cardiac dysrhythmia or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter * acute coronary syndrome and/or elective/non-elective percutaneous cardiac interventions (within 3 months) prior to randomisation or is planned to undergo any of these procedures during the study * any major cardiovascular (eg, open chest, coronary artery bypass grafting or valvular repair/replacement) or major non-cardiovascular surgery within 3 months prior to randomisation or is planned to undergo any cardiovascular surgery during the study * heart transplantation or left ventricular assist device at any time or if these are planned * kidney or any organ transplantation or if these are planned * medical conditions associated with development of hyperkalaemia (addison's disease ) * history or ongoing allergy/hypersensitivity, to sodium-glucose co-transporter-2 inhibitor (sglt2i e.g., dapagliflozin, empagliflozin) * stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within previous 3 months prior to randomisation * hepatic disease, including hepatitis and/or hepatic impairment (child-pugh class a-c), and aspartate aminotransferase or alanine transaminase or total bilirubin should be in protocol defined range at time of screening and/ or within 7 days prior to randomization * participants with newly detected pathological laboratory values or an ongoing disease condition * if the participants clinical signs and symptoms consistent with covid-19, and has been previously hospitalized with covid-19 infection and did not fully recover their previous health status * previous randomization in the present study * prior medical treatment with an mineralocorticoid receptor antagonist where the medication was taken within 90 days prior to screening * current or prior treatment within 6 months prior to screening with cytotoxic therapy, immunosuppressive therapy, or other immunotherapy

Keywords: heart failure type 2 diabetes mellitus diabetic kidney disease chronic kidney disease mineralocorticoid receptor modulator sodium-glucose co-transporter-2 inhibitor azd9977 dapagliflozin urinary albumin creatinine ratio